Italian Institute for Genomic Medicine, IIGM, 10126, Turin, Italy.
Department of Medical Sciences, University of Turin, 10126, Turin, Italy.
Arch Toxicol. 2018 May;92(5):1785-1795. doi: 10.1007/s00204-018-2179-y. Epub 2018 Mar 9.
Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involved specifically in MPM carcinogenesis need to be better clarified. To investigate asbestos-induced DNA methylation and gene expression changes, we treated Met5A mesothelial cells with different concentrations of crocidolite and chrysotile asbestos (0.5 ÷ 5.0 µg/cm, 72 h incubation). Overall, we observed 243 and 302 differentially methylated CpGs (≥ 10%) between the asbestos dose at 5 µg/cm and untreated control, in chrysotile and crocidolite treatment, respectively. To examine the dose-response effect, Spearman's correlation test was performed and significant CpGs located in genes involved in migration/cell adhesion processes were identified in both treatments. Moreover, we found that both crocidolite and chrysotile exposure induced a significant up-regulation of CA9 and SRGN (log2 fold change > 1.5), previously reported as associated with a more aggressive MPM phenotype. However, we found no correlation between methylation and gene expression changes, except for a moderate significant inverse correlation at the promoter region of DKK1 (Spearman rho = - 1, P value = 0.02) after chrysotile exposure. These results describe for the first time the relationship between DNA methylation modifications and asbestos exposure. Our findings provide a basis to further explore and validate asbestos-induced DNA methylation changes, that could influence MPM carcinogenesis and possibly identifying new chemopreventive target.
职业和环境石棉暴露是恶性胸膜间皮瘤（MPM）的主要决定因素，然而，其纤维导致细胞毒性和转化的机制尚不完全清楚。异常的 DNA 甲基化是癌症中的常见事件，但需要更好地阐明特定于 MPM 癌变的表观遗传修饰。为了研究石棉诱导的 DNA 甲基化和基因表达变化，我们用不同浓度的青石棉和温石棉石棉（0.5-5.0μg/cm，72h 孵育）处理 Met5A 间皮细胞。总体而言，我们在温石棉和青石棉处理中分别观察到 5μg/cm 剂量的石棉和未处理对照之间有 243 和 302 个差异甲基化 CpG（≥10%）。为了检查剂量反应效应，进行了 Spearman 相关检验，并在两种处理中均鉴定出位于参与迁移/细胞黏附过程的基因中的显著 CpG。此外，我们发现青石棉和温石棉暴露均诱导 CA9 和 SRGN（log2 倍数变化>1.5）的显著上调，先前报道与更具侵袭性的 MPM 表型相关。然而，我们发现除了温石棉暴露后 DKK1 启动子区域的中度显著负相关（Spearman rho=-1，P 值=0.02）外，甲基化和基因表达变化之间没有相关性。这些结果首次描述了 DNA 甲基化修饰与石棉暴露之间的关系。我们的研究结果为进一步探索和验证石棉诱导的 DNA 甲基化变化提供了基础，这些变化可能影响 MPM 癌变，并可能确定新的化学预防靶标。
